Abstract Background: OT-101 (Trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specifically inhibiting the expression of transforming growth factor-beta 2 (TGF-β2), whose overexpression is a pivotal factor for malignant progression in solid tumors. In the clinical Phase I/II study, plasma pharmacokinetic (PK) profile of OT-101 administered intravenously was evaluated in patients with advanced tumors. A population PK model was built to further understand the factors contributing to the variability in PK of OT-101. Methods: A total of 61 patients with pancreatic cancer (n=37), malignant melanoma (n=19), or colorectal carcinoma (n=5) were treated with OT-101 with escalating doses in 2 treatment schedules (1st schedule: 7-days on, 7-days off; 2nd schedule: 4-days on, 10-days off; up to 10 cycles). The PK analysis was only performed on Cycle 1 and, when applicable, Cycle 2. Blood samples were collected from patients at planned time points from before start of infusion to 7 days (1st schedule) or 10 days (2nd schedule) after stop of infusion. The plasma concentration data of OT-101 were used to build a population PK model using Phoenix NLME software. The influence of age, gender, body mass index (BMI), body weight (BW), height, cancer type, and treatment schedule as covariates on PK was evaluated. Results: With exclusion of protocol deviations, a total of 1444 plasma sample concentration data from 100 patient cycles were examined. The concentration time course of OT-101 was best described by a two-compartment model. The model estimated the PK parameters as follows: total body clearance, 0.17 mL/h; distribution volume of the central compartment, 4.69 L; inter-compartmental clearance, 3.31 L/h; distribution volume of the peripheral compartment, 5046.44 L. BW was identified as a covariate on OT-101 inter-compartmental clearance, with KBW as -ve 1.48. Conclusion: The PK parameters of OT-101 were best described by a two-compartment model. OT-101 was largely distributed in the peripheral tissues. The influence of age, gender, BMI, height, cancer type and treatment schedule on the PK of OT-101 was not identified. The model will be used for a sparse population PK study during the planned phase III trial of OT-101 in pancreatic cancer. Citation Format: Wen Wang, Kevin Ng, David Nam, Vuong Trieu, Larn Hwang. Population pharmacokinetic model for OT-101 - A TGF-β2-specific antisense oligonucleotide in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5043. doi:10.1158/1538-7445.AM2017-5043